Sulfanilyl phenyl urea complexes useful against marek&#39;s disease

ABSTRACT

Novel complexes of 4-sulfanilylphenylurea with an organic compound CONTAINING THE AMIDO LINKAGE ARE USEFUL IN THE TREATMENT AND PROPHYLAXIS OF Marek&#39;&#39;s disease.

United States ?atem 1 Ruyle [54] SULFANILYL PHENYL UREA COMPLEXES USEFULAGAINST MAREK'S DISEASE [75] Inventor: William V. Ruyle, Scotch Plains,

[73] Assignee: Merck 8: Co., lnc., Rahway, NJ. 22 Filed: April 22, 197021 Appl. No.: 31,025

[52] [1.8. Cl ..260/96.5 C, 424/244, 424/251, 424/267, 424/274, 424/322[51] Int. Cl. ..C07b 21/00 [58] Field of Search ..260/96.5 R, 96.5 U,397.6, 260/965 C, 96.5 R

11] 3,7K7fi23 [451 Feb. 20, 1973 Primary Examiner-Leon Zitver AssistantExaminerMichael W. Glynn Att0rneyl. Louis Wolk, 1 Jerome Behan andl-lesna J. Pfeiffer [57] ABSTRACT Novel complexes of4-sulfanilylphenylurea with an organic compound containing the amidolinkage o II are useful in the treatment and prophylaxis of Mareksdisease.

6 Claims, No Drawings 1 2 SULFANILYL PHENYL UREA COMPLEXES compounds isnot supported by secondary products as USEFUL AGAINST MAREK S DISEASE ischaracteristic of metathetical and substitution reactions. That thenovel addition complexes are distinct ABSTRACT OF THE INVENTION entitieshaving definite chemical composition is sup- Novel complexes having thefollowing formulas: 5 ported by the consistent analytical data and sharpmelting points of the purified products. Accordingly, the new chemicalentities of the present c invention can be depicted as follows:NH:-SOz-NH-CNHz-HN N M V V or 0 II R R Q Q A NH, -s0 NH-C-NHrHN l R/V\Rwherein each R is hydrogen or loweralkyl having one to six carbon atoms;or

v V O .7 V

H Ha) N wherein each R is hydrogen or loweralkyl having one to ll sixcarbon atoms; or

V V H t NH: SO, -NH2'(CH5)2NCR R 18 the same as above; or II a r. .v na.

so H il-NH- (CH) NH?- 2 f 2 R is the same as above; or

NHrSO2N NHrC(CH:)n

Nc o

R is the same as above, and n is an integer from 24; or

t N when R is the same as above, and m is an integer, either 2 or 4; or

0 on H l] NH s01 N- -NHz-HC on wherein R [S the same as above;

which are useful in the treatment and prophylaxis of O Mareks disease.NH so NH a NH no on The present invention encompasses a new class of y;J;

compounds which were discovered as the reaction 1 product resulting fromthe chemical combination of a R 4-sulfanilyl phenyl urea with an organiccompound containing the amido linkage 0 when R is the same as above, andm is an integer, either 2 or 4; or

Although their structure has not yet been fully elucidated, thecompounds are apparently molecular addition complexes wherein theproportion of the 4- sulfanilylphenylurea to amido-compound is in theratio C11 Nll2( of small whole numbers. This structural hypothesis issupported by the observation that formation of the Compound 1 Structuresfalling within the general formulas above include the addition complexesof 4-sulfanilylphenylurea with the various amide-organic compounds asset forth below. The structures are given in the ketotautomeric form; itwill be clear to one skilled in the art that the compounds can alsoexist in the cool tautomer.

ll HN N GHQKJ'CHZ Compound 2 (I) HN N C2H5 I H Compound 3 C OH; I 1 1:

Compound 4 3 HN N (REM-CHI Compound 5 0 N C7Hs-UC2Hs l Compound 6 CHaCompound 7 C H;

N(lJ- 0,115 O H3 Compound 8 C H;

N("3CI a C H; 0

Compound 9 CH3\ NC-C:H1 ll C 3 0 Compound 10 CII3\ N C-Cillm (J I I: 0

Compound 11 Jill /N C H; C: )II2- (I; Ii

Compound 12 (I311: on, o=o

1 l J if I Compound 13 Compound 14 Compound 15 Compound 16 Compound 17reactants are all dissolved, about 30 minutes to three hours. No solventis required when the amide-organic compound chosen is a liquid at thereaction temperature.

The reactants combine in simple molar proportions, the ratio of which isof small whole numbers, these preferably being at least one molecule ofcompletely amidocornpound per molecule of 4-sulfanilylphenylurea.

The addition complexes of this invention are useful in the treatment andprophylaxis of Marek's disease, to prevent poultry death and sickness aswell as to decrease the incidence of lymphoproliferative foci andassociated inflammatory-like lesions.

Mareks disease is a highly infections lymphoproliferative disorder ofpoultry, especially chickens. Mareks disease has also been known asneural leukosis. The causative agent(s) are viral with a DNA-type virusimplicated as an etiological factor. Mareks disease often is clinicallyevident in birds prior to sexual maturity, i.e., before the first egg islaid. Clinical manifestations may be one or more of these signs:regional or generalized paralysis, diarrhea with fecal staining ofposterior abdominal feathers, weight loss, dyspnea, blindness, enlargedabdomen or death.

The lesions evident are one or more of the following: lymphocyticinfiltrated peripheral nerves and/or feather follicles;lymphoproliferative lesions, microscopic to several mm. in size, withinany tissue of the body but principally within the liver, spleen, kidney,gonads, heart, proventriculus, breast muscle, skin, and nerves.

Mareks disease is estimated by the U. S. Department of Agriculture tocause a $200 million annual loss to the US. poultry industry. This lossis due to mortality and morbidity and to the rejection of slaughteredbird carcasses as being unfit for human consumption. This rejection isdue to the presence of the lymphoproliferative foci.

In this connection, the compounds have proved effective against Mareksdisease when orally administered to chickens at a dosage level of 0.0020.1 percent by weight, based on the amount of the compounds in thechicken feed. The compounds can also be administered orally via thedrinking water, in levels of 0.0001 to 0.01 percent by weight. Anextremely useful and unexpected asset of these addition complexes istheir solubility in water and other polar solvents, making them easy toadminister via the poultry drinking water route.

The compounds can also be utilized in feed supplement compositionscontaining from about 2 to 40 percent by weight of the compounds. About1-5 pounds of this supplement is mixed in a ton of poultry feed by theindustry to obtain the desired use level.

Diluent or carrier vehicles that may be used in these poultry feedsupplements are solid orally ingestible poultry feed additives such ascorn meal, distillers dried grains, ground oyster shell, citrus mealfermantation residues, wheat shorts, wheat middlings, molasses solubles,corn gluten feed, soybean meal, dehulled soya flour, crushed limestone,fermentation mycelia, edible vegetable substances and the like.Nutritive carriers are preferred since the finished feed is benefittedthereby.

Examples of typical feed supplements containing the compound ofthe.present invention are Lbs. 4-sulfanily1phenylurea 4,6-dimethyl-2-hydroxy pyrimidine 3.0 Amprolium 25.0 Wheat middlings 72.04-sulfani1ylphenylurea N,N-

dimethylacetamide 5.0 Corn gluten feed 95.0

(C) 4-sulfanilylphenylurea 1-methyl-2- pyrrolidinone 20.0 Com germ meal40.0 Corn distillers' grains 40.0

The following examples serve to illustrate this invention.

EXAMPLE 1 4-Sulfanilylphenylurea 4,6-dimethyl-2-hydroxy pyrimidine Asuspension of 485 mg. of 4-(N-sulfanilyl) phenylurea in 5 ml. ofdimethoxyethane is heated on the steam bath, and 267 mg. of4,6-dimethy1-2-hydroxy pyrimidine is added with stirring. Nearlycomplete solution ensues, followed by precipitation of the complex. Themixture is heated at reflux for a few minutes, then cooled, and thecomplex collected by filtration. The yield of4-sulfanilyphenylurea-4,6-dimethy1-2-hydroxy pyrimidine is 570 mg., m.p.l93-l95C. Anal. Calcd. for C H N O S: C, 54.93; H 5.10; N, 16.86. Found:C,55.39; H, 5.22; N, 16.89. The NMR spectrum in deuteriodimethylsulfoxide is also indicative of a 1:1 complex.

EXAMPLE 2 EXAMPLE 3 4-Sulfanilylphenylurea 'N,N-dimethylacetamide Usingthe same procedure as in Example 2, 4-(N- sulfanilyl)phenylurea isheated in N,N-dimethylacetamide. A 1:1 complex is obtained having amelting point of l05l08C., identified as 4-sulfanilylphenylurea'N,N-dimethylacetamide.

EXAMPLE 4 4-Sulfanilylphenylurea '1-methyl-2-pyrrolidinone To a solutionof 200 mg. of 4-(N-sulfanilyl)phenylurea in 0.5 ml. ofl-methyl-2-pyrrolidinone is added 2 ml. of acetone and 10 ml. of ether.The 1:1 complex separates as an oil, which crystallizes gradually, m.p.C. with prior softening.

EXAMPLE 5 4-Sulfanilylphenylurea 1-methy1-2-pyridone Using the sameprocedure as Example 4, 4-(N- sulfanilyl)phenylurea is heated withl-methyl-2- pyridone. A 1:1 complex is obtained having a melting pointof 142-l44C., identified as 4-sulfani1ylphenylurea l-methyl-Z-pyridone.

What is claimed is:

1. A novel complex chosen from the group consisting of wherein each R ishydrogen or loweralkyl having one to six carbon atoms;

wherein R is the same as above;

wherein R is the same as above, and n is an integer from 2-4;

ll NHz- -s0= NH-o-NH,-Ho /c=0 N l R wherein R is the same as above;

[1 HC CH NHQ s02 NH-C-NHz- II wherein R is the same as above; and i 0 OHH H NH?" so! -N-CNHz-HC\\ on each R being hydrogen or loweralkyl havingone to six carbon atoms.

3. The complex of claim 1 in which the organic compound is R beinghydrogen or loweralkyl having one to six carbon atoms.

4. The complex of claim 1 in which the organic compound is R beinghydrogen or loweralkyl having one to six carbon atoms, and n being aninteger from 2-4.

5. The complex of claim 1 in which the organic compound is H on & HO OHHO 0:0 or ll 4:

i N R R being hydrogen or loweralkyl having one to six carbon atoms,

6. The complex of claim 1 in which the organic compound is

1. A novel complex chosen from the group consisting of wherein each R ishydrogen or loweralkyl having one to six carbon atoms; wherein R is thesame as above; wherein R is the same as above, and n is an integer from2-4; wherein R is the same as above;
 2. The complex of claim 1 in whichthe organic compound is each R being hydrogen or loweralkyl having oneto six carbon atoms.
 3. The complex of claim 1 in which the organiccompound is R being hydrogen or loweralkyl having one to six carbonatoms.
 4. The complex of claim 1 in which the organic compound is Rbeing hydrogen or loweralkyl having one to six carbon atoms, and n beingan integer from 2-4.
 5. The complex of claim 1 in which the organiccompound is R being hydrogen or loweralkyl having one to six carbonatoms,